High Fischer ratio oligopeptides (HFROs) are a group of oligopeptides containing high levels of branched-chain amino acids (BCAA) and low levels of aromatic amino acids (AAA). HFROs have received a lot of attention as they are believed to have significant physiological activities, including antioxidant, liver damage repair, anti-fatigue, anti-tumor and energy supply to the body. HFROs are available from a wide range of sources and both plant and animal proteins can be used to prepare HFROs but the physiological tolerability and rejection of special populations needs to be considered. Enzymatic hydrolysis is the most common method for the preparation of HFROs, but optimization of the separation and purification process is still needed in the future. Diseases caused by disruptions in the balance of BCAA and AAA in the blood, such as hepatic encephalopathy, can be treated by supplementing HFROs with drugs or food. In addition, HFROs are able to reduce fatigue feedback and assist in the treatment of phenylketonuria at the molecular nutrient level. The aim of this review is to review recent research on HFROs and provide new perspectives on the high value use of crops and the development of novel functional and special medical purpose foods.